Abstract
A new series of pyrimidine derivatives was designed and synthesized from 2-thiouracil via multicomponent, Biginelli-type reactions and structurally characterized by all spectral means. Synthesized compounds were evaluated for antiproliferative activity against Ehrlich ascites tumour (EAT) cells. A molecular docking study was carried out to establish the binding mode of these compounds into human casein kinase-2 inhibitor (CK2). The established binding modes of these compounds into human CK2 were in very good agreement with the in vitro antiproliferative activity. Compound 4-(2-(1H-indol-2-yl)ethylamino)-2-(2-(diethylamino)ethylthio)-6-(4-fluorophenyl)pyrimidine-5-carbonitrile 4h exhibited stronger cytotoxic activity against EAT cells with an IC50 value of 5.2 µM which was the nearest cytotoxic activity compared with the standard drug methotrexate (MTX) that showed an IC50 value of 3.6 µM. Compound 4h has the maximum cytotoxicity against EAT cell, the lowest binding energy (−8.7 kcal/mol) and good ligand efficiency with CK2 compared to all other compounds.
Similar content being viewed by others
References
M. Hussein, O.M. Ahmed, Bioorg. Med. Chem. Lett. 18, 2639 (2010)
S. Schenone, O. Bruno, F. Bondavalli, A. Ranise, G. Menozzi, P. Fossa, S. Donnini, A. Santoro, L. Mosti, M. Ziche, F. Manetti, M. Botta, Eur. J. Med. Chem. 39, 939 (2004)
H. Sun, X. Guo, S. Zhang, X. Xu, J. Huang, Z. Liu, X. Wu, Z. Jiang, X. Zhang, T. Feng, Q. You, J. Chem. Inf. Model. 53, 2093 (2013)
D. Drygin, S.E. O’brien, K.L. Anderes, D. Von Hoff, J.K.C. Lim, C.S. Padgett, J.R. Bliesath, C.B. Ho, W.G. Rice, US 20110212845 A1 (2011)
C. Hundsdörfer, H.J. Hemmerling, J. Hamberger, M. Le Borgne, P. Bednarski, C. Götz, F. Totzke, J. Jose, Biochem. Biophys. Res. Commun. 424, 71 (2012)
A.G. Golub, V.G. Bdzhola, N.V. Briukhovetska, A.O. Balanda, O.P. Kukharenko, I.M. Kotey, O.V. Ostrynska, S.M. Yarmoluk, Eur. J. Med. Chem. 46, 870 (2011)
E. Vangrevelinghe, K. Zimmermann, J. Schoepfer, R. Portmann, D. Fabbro, P. Fure, J. Med. Chem. 46, 2656–2662 (2003)
G.J. Gozzi, Z. Bouaziz, E. Winter, N. Daflon-Yunes, D. Aichele, A. Nacereddine, C. Marminon, G. Valdameri, W. Zeinyeh, A. Bollacke, J. Guillon, A. Lacoudre, N. Pinaud, S.M. Cadena, J. Jose, M. Le Borgne, A.D. Pietro, J. Med. Chem. 58, 265 (2015)
M.A.M.S. El-Sharief, Z. Moussa, A.M.S. El-Sharief, J. Fluor. Chem. 160, 82 (2014)
P.J. Chen, A. Yang, Y.F. Gu, X.S. Zhang, K.P. Shao, D.Q. Xue, P. He, T.F. Jiang, Q.R. Zhang, H.M. Liu, Bioorg. Med. Chem. Lett. 24, 2741 (2014)
E.S. Al-Abdullah, A.R.M. Al-Obaid, O.A. Al-Deeb, E.E. Habib, A. El-Emam, Eur. J. Med. Chem. 46, 4642 (2011)
A.P. Keche, G.D. Hatnapure, R.H. Tale, A.H. Rodge, S.S. Birajdar, V.M. Kamble, Bioorg. Med. Chem. Lett. 22, 3445 (2012)
A. Ozair, M. Pooja, S.P. Verma, J.G. Sadaf, A.K. Suroor, S. Nadeem, A. Waquar, Eur. J. Med. Chem. 45, 2467 (2010)
H.T. Abdel-Mohsen, A.F.R. Fatma, M.R. Mostafa, I.E.D. Hoda, Eur. J. Med. Chem. 45, 2336 (2010)
D. Xianming, N. Advait, W. Tao, S. Tomoyo, H. Kerstin, C. Zhong, K. Kelli, P. David, W. Elizabeth, A. Francisco, T. Tove, C. Jonathan, S. Susan, H. Steven, E. Jared, I. John, C.T. David, K.C. Arnab, S.G. Nathanael, Bioorg. Med. Chem. Lett. 20, 4027 (2010)
P. Nagender, G.M. Reddy, R.N. Kumar, Y. Poornachandra, C.G. Kumar, B. Narsaiah, Bioorg. Med. Chem. Lett. 24, 2905 (2014)
T.G. Kraljevic, N. Ilic, V. Stepanic, L. Sappe, J. Petranovic, S.K. Pavelic, S. Raic-Malic, Bioorg. Med. Chem. Lett. 24, 2913 (2014)
A.B. Siddiqui, A.R. Trivedi, V.B. Kataria, V.H. Shah, Bioorg. Med. Chem. Lett. 24, 1493 (2014)
W.Y. Mo, Y.J. Liang, Y.C. Gu, L.W. Fu, H.W. He, Bioorg. Med. Chem. Lett. 21, 5975 (2011)
Z. Liu, Y. Wang, H. Lin, D. Zuo, L. Wang, Y. Zhao, P. Gong, Eur. J. Med. Chem. 85, 215 (2014)
A.M. Shamsuzzaman, S. Dar, M. Tabassum, Y. Zaki, A. Khan, M.A. Sohail, C.R. Gatoo, Chimie 17, 359 (2014)
L.Y. Ma, L.P. Pang, B. Wang, M. Zhang, B. Hu, D.Q. Xue, K.P. Shao, B.L. Zhang, Y. Liu, E. Zhang, H.M. Liu, Eur. J. Med. Chem. 86, 368 (2014)
S. Tardy, A. Orsato, L. Mologni, W.H. Bisson, C. Donadoni, C.G. Passerini, L. Scapozza, D. Gueyrard, P.G. Goekjian, Bioorg. Med. Chem. 22, 1303 (2014)
A. Mollard, S.L. Warner, L.T. Call, M.L. Wade, J.J. Bearss, A. Verma, S. Sharma, H. Vankayalapati, D.J. Bearss, A.C.S. Med, Chem. Lett. 2, 907 (2011)
M.T. Burger, M. Knapp, A. Wagman, Z. Ni, T. Hendrickson, G. Atallah, Y. Zhang, K. Frazier, J. Verhagen, K. Pfister, S. Ng, A. Smith, S. Bartulis, H. Merrit, M. Weismann, X. Xin, J. Haznedar, C.F. Voliva, E. Iwanowicz, S. Pecchi, A.C.S. Med, Chem. Lett. 2, 34 (2011)
D. Buttar, M. Edge, S.C. Emery, M. Fitzek, C. Forder, A. Griffen, B. Hayter, C.F. Hayward, P.J. Hopcroft, R.W. Luke, K. Page, J. Stawpert, A. Wright, Bioorg. Med. Chem. Lett. 18, 4723 (2008)
J.J. Chen, K.D. Thakur, M.P. Clark, S.K. Laughlin, K.M. George, R.G. Bookland, J.R. Davis, E.J. Cabrera, V. Easwaran, B. De, Y.G. Zhang, Bioorg. Med. Chem. Lett. 16, 5633 (2006)
M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A.M. Farag, Eur. J. Med. Chem. 46, 3690 (2011)
A.K. Bhattacharjee, J.W. Pomponio, S.A. Evans, D. Pervitsky, R.K. Gordon, Bioorg. Med. Chem. 21, 2651 (2013)
J. Lavrado, K. Gani, P.A. Nobre, S.A. Santos, P. Figueiredo, D. Lopes, V. Rosário, J. Gut, P.J. Rosenthal, R. Moreira, A. Paulo, Bioorg. Med. Chem. Lett. 20, 5634 (2010)
C. Moura, L. Gano, F. Mendes, P.D. Raposinho, A.M. Abrantes, M.F. Botelho, I. Santos, A. Paulo, Eur. J. Med. Chem. 50, 350 (2012)
A. De Fatima Pereira, V.M. da Costa, M.C.M. Santos, F.C. Horta Pinto, G.R. da Silva, Biomed. Pharmacother. 68, 365–368 (2014)
A. Stella, K.V. Belle, S.D. Jonghe, T. Louat, J. Herman, J. Rozenski, M. Waer, P. Herdewijn, Bioorg. Med. Chem. 21, 1209 (2013)
S.B. Mohan, B.V.V.R. Kumar, S.C. Dinda, D. Naik, S.P. Seenivasan, V. Kumar, D.N. Rana, P.S. Brahmkshatriya, Bioorg. Med. Chem. Lett. 22, 7539 (2012)
S.A. Galal, A.S. Abdelsamie, H. Tokuda, N. Suzuki, A. Lida, M.M. ElHefnawi, R.A. Ramadan, M.H.E. Atta, H.I. El Diwani, Eur. J. Med. Chem. 46, 327 (2011)
G.J.L. Bernardes, J.M. Chalker, J.C. Errey, B.G. Davis, J. Am. Chem. Soc. 130, 5052 (2008)
V.J. Gray, J. Cuthbertson, J.D. Wilden, J. Org. Chem. 79, 5869 (2014)
T.P. Petersen, A.F. Larsen, A. Ritzén, T. Ulven, J. Org. Chem. 78, 4190 (2013)
T. Indumathi, A. Muthusankar, P. Shanmughavel, K.J. Rajendra Prasad, Med. Chem. Commun. 4, 450 (2013)
A.Y. Lukmantara, D.S. Kalinowski, N. Kumar, D.R. Richardson, Org. Biomol. Chem. 11, 6414 (2013)
K.F. Ansari, C. Lal, Eur. J. Med. Chem. 44, 4028 (2009)
L.P. Shi, K.M. Jiang, J.J. Jiang, Y. Jin, Y.H. Tao, K. Li, X.H. Wang, J. Lin, Bioorg. Med. Chem. Lett. 23, 5958 (2013)
A. Guan, C. Liu, G. Huang, H. Li, S. Hao, Y. Xu, Y. Xie, Z. Li, J. Fluor. Chem. 160(2014), 82 (2014)
J. Matysiak, Eur. J. Med. Chem. 42, 940 (2007)
M.M.F. Ismail, H.S. Rateb, M.M.M. Hussein, Eur. J. Med. Chem. 45, 3950 (2010)
K.M. Kumar, P. Anitha, V. Sivasakthi, S. Bag, P. Lavanya, A. Anbarasu, S. Ramaiah, 3 Biotech 4, 241 (2014)
Acknowledgments
The authors thank the management of VIT University, Vellore for all the support and encouragement. In addition the support from SAIF, School of Advanced Sciences, VIT University, Vellore and DST-FIST is greatly acknowledged for the spectral analysis.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Senthilkumar, N., Ravichandran, Y.D., Kumar, K.M. et al. Synthesis of a new series of pyrimidine derivatives: exploration of anti-proliferative activity on EAT cells and molecular docking. Res Chem Intermed 42, 1295–1313 (2016). https://doi.org/10.1007/s11164-015-2086-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11164-015-2086-2